5-Ht7 Receptor Antagonists

ABSTRACT

The invention relates to compounds having pharmacological activity towards the 5-HT7 receptor, and more particularly to some tetrahydroisoquinoline substituted sulfonamide compounds, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment and or prophylaxis of a disease in which 5-HT is involved, such as CNS disorders.

FIELD OF THE INVENTION

The present invention relates to compounds having pharmacologicalactivity towards the 5-HT7 receptor, and more particularly to sometetrahydroisoquinoline substituted sulfonamide compounds, to processesof preparation of such compounds, to pharmaceutical compositionscomprising them, and to their use in therapy, in particular for thetreatment and or prophylaxis of a disease in which 5-HT₇ is involved,such as CNS disorders.

BACKGROUND OF THE INVENTION

The search for new therapeutic agents has been greatly aided in recentyears by better understanding of the structure of proteins and otherbiomolecules associated with target diseases. One important class ofproteins that has been the subject of extensive study is the family of5-hydroxytryptamine (serotonin, 5-HT) receptors. The 5-HT₇ receptordiscovered in 1993 belongs to this family and has attracted greatinterest as a valuable new drug target (Terrón, J. A. Idrugs, 1998, vol.1, no. 3, pages 302-310: “The 5HT ₇ receptor: 4 target for noveltherapeutic avenues?”).

5-HT₇ receptors have been cloned from rat, mouse, guinea pig and humancDNA and exhibit a high degree of interspecies homology (approx. 95%),but it is unique in that it has a low sequence homology with other 5-HTreceptors (less than 40%). Its expression pattern, in particularstructures of the central nervous system (CNS) (highest in hypothalamus(in particular suprachiasmatic nuclei) and thalamus) and otherperipheral tissues (spleen, kidney, intestinal, heart and coronaryartery), implicates the 5-HT₇ receptor in a variety of functions andpathologies. This idea is reinforced by the fact that severaltherapeutic agents, such as tricyclic antidepressants, typical andatypical antipsychotics and some 5-HT₂ receptor antagonists, displaymoderate to high affinity for both recombinant and functional 5-HT₇receptors.

Functionally, the 5-HT₇ receptor has been implicated in regulation ofcircadian rhythms in mammals (Lovenberg, T. W. et al. Neuron, 1993,11:449-458 “A novel adenylyl cyclase-activating serotonin receptor (5-HT₇) implicated in the regulation of circadian rhythms”). It is known thatdisruption of circadian rhythms is related to a number of CNS disordersincluding depression, seasonal affective disorder, sleep disorders,shift worker syndrome and jet lag among others.

Distribution and early pharmacological data also suggest that the 5-HT₇receptor is involved in the vasodilatation of blood vessels. This hasbeen demonstrated in vivo (Terrón, J. A., Br J Pharmacol, 1997,121:563-571 “Role of 5-HT ₇ receptors in the long lasting hypotensiveresponse induced by 5-hydroxytryptamine in the rat”). Thus selective5-HT₇ receptor agonists have a potential as novel hypertensive agents.

The 5-HT₇ receptor has also been related with the pathophysiology ofmigraine through smooth muscle relaxation of cerebral vessels(Schoeffler, P. et al., 1996, Br J Pharmacol, 117:993-994; Terrón, J.A., 2002, Eur. J. Pharmacol., 439:1-11 “Is the 5-HT ₇ receptor involvedin the pathogenesis and prophylactic treatment of migraine?”). In asimilar manner, involvement of 5-HT₇ in intestinal and colon tissuesmooth muscle relaxation makes this receptor a target for the treatmentof irritable bowel syndrome (De Ponti, F. et al., 2001, Drugs,61:317-332 “Irritable bowel syndrome. New agents targeting serotoninreceptor subtypes”). Recently, it has also been related to urinaryincontinence (British J. of Pharmacology, September 2003, 140(1) 53-60:“Evidence for the involvement of central 5HT-7 receptors in themicurition reflex in anaesthetized female rats”).

In view of the potential therapeutic applications of agonists orantagonists of the 5HT₇ receptor, a great effort has been directed tofind selective ligands. Despite intense research efforts in this area,very few compounds with selective 5-HT₇ antagonist activity have beenreported (Wesolowska, A., Polish J Pharmacol., 2002, 54: 327-341, “Inthe search for selective ligands of 5-HT ₅, 5-HT ₆ and 5-HT ₇ serotoninreceptors”).

WO 97/48681 discloses sulfonamide derivatives, which are 5-HT₇ receptorantagonists, for the treatment of CNS disorders. The sulphur atom islinked to an aromatic group and to a N-containing heterocyclic group,optionally containing a further heteroatom selected from oxygen orsulphur.

WO 97/29097 describes sulfonamide derivatives for the treatment ofdisorders in which antagonism of the 5-HT₇ receptor is beneficial. Thesulphur atom is linked to an aromatic group and to a C₁-C₆ alkylsubstituted N atom.

WO97/49695 describes further sulfonamide derivatives in which the Nlinked to the sulphur atom is also fully substituted, for exampleforming part of a piperidine.

WO 03/048118 describes another group of 5HT₇ receptor antagonists. Inthis case aryl and heteroaryl sulfonamide derivatives wherein thesulfonamide group is a substituent on a cycloalkane or cycloalkene ringwhich additionally bears an amino substituent. The N linked to sulphuratom is fully substituted.

WO99/24022 discloses tetrahydroisoquinoline derivatives for use againstCNS disorders and binding to serotonin receptors, in particular 5-HT₇.

WO 00/00472 refers to compounds which are 5-HT₇ receptor antagonists.The compounds contain a N-containing fused heterocycle such astetrahydroisoquinoline.

EP 21580 and EP 76072 describe sulfonamide compounds havingantiarrhythmic activity, corresponding to the formulaR₂N(CH₂)_(n)—NH—SO₂R₁, 5-HT₇ activity is not mentioned.

There is still a need to find compounds that have pharmacologicalactivity towards the receptor 5-HT₇, being both effective and selective,and having good “drugability” properties, i.e. good pharmaceuticalproperties related to administration, distribution, metabolism andexcretion.

SUMMARY OF THE INVENTION

We have now found a family of structurally distinct class of sulfonamidecompounds which are particularly selective inhibitors of the 5-HT₇receptor. The compounds present a tetrahydroisoquinoline moiety, linkedthrough a 3, or 4-methylene piperidine with a sulfonamide moiety. Wehave found that the compounds display IC-50 values in the nM range(10-100 nM) at human 5-HT7 receptors and exhibit selectivity for thesereceptors vs 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, D1,D2, D3, D4, adrenergic α1A, α1B, α1B, β1, and β2 receptors.

In one aspect the invention is directed to a compound of the formula I:

whereinW is a substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heterocyclyl;R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are each independently selected from thegroup formed by hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted aryl, substituted or unsubstitutedheterocyclyl, —COR⁸, —C(O)OR⁸, —C(O)NR⁸R⁹, —HC═NR⁸, —CN, —OR⁸, —OC(O)R⁸,—S(O)_(t)—R⁸, —NR⁸R⁹, —NR⁸C(O)R⁹, —NO₂, —N═CR⁸R⁹ or halogen; whereint is 1, 2 or 3;R⁸ and R⁹ are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkenyl, substituted or unsubstituted aryl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted aryloxy, halogen;and wherein the 1,2,3,4-tetrahydroisoquinoline group is linked throughmetilene to positions 3 or 4 of the piperidine ring.or a pharmaceutically acceptable salt, isomer, prodrug or solvatethereof.

In another aspect the invention is directed to a pharmaceuticalcomposition which comprises a compound as above defined or apharmaceutically acceptable salt, enantiomer, prodrug or solvatethereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

In a further aspect the invention is directed to the use of a compoundas defined above in the manufacture of a medicament for the treatment ofa 5-HT₇ mediated disease or condition, i.e. diseases caused by failuresin central and peripheral serotonin-controlling functions, such as pain,sleep disorder, shift worker syndrome, jet lag, depression, seasonalaffective disorder, migraine, anxiety, psychosis, schizophrenia,cognition and memory disorders, neuronal degeneration resulting fromischemic events, cardiovascular diseases such as hypertension, irritablebowel syndrome, inflammatory bowel disease, spastic colon or urinaryincontinence.

DETAILED DESCRIPTION OF THE INVENTION

The typical compounds of this invention effectively and selectivelyinhibit the 5-HT7 receptor vs. other 5-HT receptors such as 5-HT1A,5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, D1, D2, D3, D4, adrenergicα1A, α1B, α1b, β1, and β2 receptors, Tachykinin NK-1 opiate, GABA,estrogen, glutamate, adenosine, nicotinic, muscarinic receptors andcalcium, potassium and sodium channels and neurotransmitter transporters(serotonin, dopamine, norepinephrine, GABA).

In the above definition of compounds of formula (I) the following termshave the meaning indicated:

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting of carbon and hydrogen atoms, containing no saturation,having one to eight carbon atoms, and which is attached to the rest ofthe molecule by a single bond, e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, n-pentyl, etc. Alkyl radicals may be optionallysubstituted by one or more substituents such as a aryl, halo, hydroxy,alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro,mercapto, alkylthio, etc. If substituted by aryl we have an “Aralkyl”radical, such as benzyl and phenethyl.

“Alkenyl” refers to an alkyl radical having at least 2 C atoms andhaving one or more unsaturated bonds.

“Cycloalkyl” refers to a stable 3- to 10-membered monocyclic or bicyclicradical which is saturated or partially saturated, and which consistsolely of carbon and hydrogen atoms, such as cyclohexyl or adamantyl.Unless otherwise stated specifically in the specification, the term“cycloalkyl” is meant to include cycloalkyl radicals which areoptionally substituted by one or more substituents such as alkyl, halo,hydroxy, amino, cyano, nitro, alkoxy, carboxy, alkoxycarbonyl, etc.

“Aryl” refers to single and multiple ring radicals, including multiplering radicals that contain separate and/or fused aryl groups. Typicalaryl groups contain from 1 to 3 separated or fused rings and from 6 toabout 18 carbon ring atoms, such as phenyl, naphthyl, indenyl,fenanthryl or anthracyl radical. The aryl radical may be optionallysubstituted by one or more substituents such as hydroxy, mercapto, halo,alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino,aminoalkyl, acyl, alkoxycarbonyl, etc.

“Heterocyclyl” refers to a stable 3- to 15 membered ring radical whichconsists of carbon atoms and from one to five heteroatoms selected fromthe group consisting of nitrogen, oxygen, and sulfur, preferably a 4- to8-membered ring with one or more heteroatoms, more preferably a 5- or6-membered ring with one or more heteroatoms. For the purposes of thisinvention, the heterocycle may be a monocyclic, bicyclic or tricyclicring system, which may include fused ring systems; and the nitrogen,carbon or sulfur atoms in the heterocyclyl radical may be optionallyoxidised; the nitrogen atom may be optionally quaternized; and theheterocyclyl radical may be partially or fully saturated or aromatic.Examples of such heterocycles include, but are not limited to, azepines,benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole,piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran,coumarine, morpholine; pyrrole, pyrazole, oxazole, isoxazole, triazole,imidazole, etc.

“Alkoxy” refers to a radical of the formula —ORa where Ra is an alkylradical as defined above, e.g., methoxy, ethoxy, propoxy, etc.

“Alkoxycarbonyl” refers to a radical of the formula —C(O)ORa where Ra isan alkyl radical as defined above, e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, etc.

“Alkylthio” refers to a radical of the formula —SRa where Ra is an alkylradical as defined above, e.g., methylthio, ethylthio, propylthio, etc.

-   -   “Amino” refers to a radical of the formula —NH₂, —NHRa or        —NRaRb, optionally quaternized.

“Halo” or “hal” refers to bromo, chloro, iodo or fluoro.

References herein to substituted groups in the compounds of the presentinvention refer to the specified moiety that may be substituted at oneor more available positions by one or more suitable groups, e.g.,halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro;azido; alkanoyl such as a C1-6 alkanoyl group such as acyl and the like;carboxamido; alkyl groups including those groups having 1 to about 12carbon atoms or from 1 to about 6 carbon atoms and more preferably 13carbon atoms; alkenyl and alkynyl groups including groups having one ormore unsaturated linkages and from 2 to about 12 carbon or from 2 toabout 6 carbon atoms; alkoxy groups having one or more oxygen linkagesand from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms;aryloxy such as phenoxy; alkylthio groups including those moietieshaving one or more thioether linkages and from 1 to about 12 carbonatoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups includingthose moieties having one or more sulfinyl linkages and from 1 to about12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl groupsincluding those moieties having one or more sulfonyl linkages and from 1to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkylgroups such as groups having one or more N atoms and from 1 to about 12carbon atoms or from 1 to about 6 carbon atoms; carbocylic aryl having 6or more carbons, particularly phenyl or naphthyl and aralkyl such asbenzyl. Unless otherwise indicated, an optionally substituted group mayhave a substituent at each substitutable position of the group, and eachsubstitution is independent of the other.

Particular individual compounds of the invention include the compoundsI-78 in the examples, either as salts or as free bases.

In an embodiment the tetrahydroisoquinoline in the compounds of formulaI above is not substituted, R¹ to R⁷ are all H. Good activity resultsare obtained with such compounds.

In another embodiment R² is alkoxy, preferably methoxy and the rest ofthe substitutents of the tetrahydroisoquinoline (R¹ and R³ to R⁷) are H.

In another embodiment R² and R³ are alkoxy, preferably methoxy and therest of the substitutents of the tetrahydroisoquinoline (R¹ and R⁴ toR⁷) are H.

In another embodiment the group W linked to the sulfonamide is aromatic,such as substituted or unsubstituted aryl, substituted or unsubstitutedheterocyclyl, preferably substituted or unsubstituted phenyl. Goodresults were obtained when W is alkyl, alkoxy and/or halo substitutedphenyl. In particular halo substituted phenyl, having one or more halosubstituents being the same or different are preferred.

In an embodiment it is important that 1,2,3,4-tetrahydroisoquinolinegroup is linked through metilene to position 4 of the piperidine ring.Best results were obtained with this position linking thetetrahydroisoquinoline.

The above embodiments and preferences for W, R¹ to R⁷ and the positionof linkage can be combined to give farther preferred compounds.

Representative compounds of the above embodiments which are preferredare: 2-[1-(5-Chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroiso-quinolinehydrochloride,2-[1-(2-Chloro-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride,2-[1-(2,5-Dichloro-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride,2-[1-(Toluene-3-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride,2-[1-(2-Chloro-4,5-difluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydro-chloride,2-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride,2-[1-(2-Bromo-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride,2-[1-(Naphtalene-1-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride.

The compounds of the present invention represented by the abovedescribed formula (I) may include enantiomers depending on the presenceof chiral centres or isomers depending on the presence of multiple bonds(e.g. Z, E). The single isomers, enantiomers or diastereoisomers andmixtures thereof fall within the scope of the present invention.

Unless otherwise stated, the compounds of the invention are also meantto include compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by a ¹³C- or 14C-enriched carbonor ¹⁵N-enriched nitrogen are within the scope of this invention.

The term “pharmaceutically acceptable salts, solvates, prodrugs” refersto any pharmaceutically acceptable salt, ester, solvate, or any othercompound which, upon administration to the recipient is capable ofproviding (directly or indirectly) a compound as described herein.However, it will be appreciated that non-pharmaceutically acceptablesalts also fall within the scope of the invention since those may beuseful in the preparation of pharmaceutically acceptable salts. Thepreparation of salts, prodrugs and derivatives can be carried out bymethods known in the art.

For instance, pharmaceutically acceptable salts of compounds providedherein are synthesized from the parent compound which contains a basicor acidic moiety by conventional chemical methods. Generally, such saltsare, for example, prepared by reacting the free acid or base forms ofthese compounds with a stoichiometric amount of the appropriate base oracid in water or in an organic solvent or in a mixture of the two.Generally, nonaqueous media like ether, ethyl acetate, ethanol,isopropanol or acetonitrile are preferred. Examples of the acid additionsalts include mineral acid addition salts such as, for example,hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate,and organic acid addition salts such as, for example, acetate, maleate,fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate,methanesulphonate and p-toluenesulphonate. Examples of the alkaliaddition salts include inorganic salts such as, for example, sodium,potassium, calcium, ammonium, magnesium, aluminium and lithium salts,and organic alkali salts such as, for example, ethylenediamine,ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glucamine andbasic aminoacids salts.

Particularly favored derivatives or prodrugs are those that increase thebioavailability of the compounds of this invention when such compoundsare administered to a patient (e.g., by allowing an orally administeredcompound to be more readily absorbed into the blood) or which enhancedelivery of the parent compound to a biological compartment (e.g., thebrain or lymphatic system) relative to the parent species.

Any compound that is a prodrug of a compound of formula (I) is withinthe scope of the invention. The term “prodrug” is used in its broadestsense and encompasses those derivatives that are converted in vivo tothe compounds of the invention. Such derivatives would readily occur tothose skilled in the art, and include, depending on the functionalgroups present in the molecule and without limitation, the followingderivatives of the present compounds: esters, amino acid esters,phosphate esters, metal salts sulfonate esters, carbamates, and amides.

The compounds of the invention may be in crystalline form either as freecompounds or as solvates and it is intended that both forms are withinthe scope of the present invention. Methods of solvation are generallyknown within the art. Suitable solvates are pharmaceutically acceptablesolvates. In a particular embodiment the solvate is a hydrate.

The compounds of formula (I) or their salts or solvates are preferablyin pharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, having apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels. Purity levels for thedrug substance are preferably above 50%, more preferably above 70%, mostpreferably above 90%. In a preferred embodiment it is above 95% of thecompound of formula (I), or of its salts, solvates or prodrugs.

The compounds of formula (I) defined above can be obtained by availablesynthetic procedures.

Compounds of Formula (Ia) or (Ib) can be prepared by the coupling ofcompounds of Formula (IIa) or (IIb):

in which R¹-R⁷ are as defined in Formula (I), with a compound of Formula(III):

in which W is as defined in Formula (I) and X is an halogen, typicallyCl.

The reaction of compounds of formulas (II) and (III) is preferablycarried out in an aprotic solvent, but not limited to, such asdichloromethane in the presence of an organic base, such asdiisopropylethylamine or triethylamine.

Compounds of Formula (III) are commercially available or can be preparedby conventional methods.

Compounds of Formula (II) can be commercially available or prepared fromcompounds of Formula (IV). Compounds of Formula (IV) can also becommercially available or synthesized by conventional methods, such asPictet-Spengler reaction from substituted phenylethyl amines and ketonesor aldehydes substituted with R⁵, as shown in Scheme 1.

Compounds of Formula (II) can be synthesized by the methods describedbelow. The reactions are performed in a solvent appropriate to thereagents and materials employed and suitable for the transformations.The functionality present on the molecule should be consistent with thetransformations proposed. This will sometimes require a selection of aparticular process scheme over another in order to obtain the desiredcompound of the invention. Preferred methods included, but are notlimited to, those described below.

Compounds of Formula (II) can be prepared by an amide formation fromcompounds of Formula (IV) and a isonipecotic acid(piperidine-4-carboxylic acid, Va) derivative or nipecotic acid(piperidine-3-carboxylic acid, Vb) derivative, which should have theamino group-protected, to give an intermediate of Formula (VI), followedby a deprotection of the amino group and a reduction of the amido group,as shown in Scheme 2. The commercially available acid derivatives (Va)and (Vb) with the amino group protected are those with a carbamate, suchas BOC or CBZ, or with a benzyl group.

If Z=OH, the amidation can be performed by the activation of thecarboxylic acid with a carbodiimide, such as1,1-dicyclohexylcarbodiimide (DCC) or 1-Ethyl 3-(3-dimethylaminopropyl)carbodiimide (EDC), in the presence of a catalytic amount of anorganic base, such as DMAP or HOBT in an appropriate solvent, such asdichloromethane or N,N-dimethylformamide.

The amidation can also be achieved using piperidinecarbonyl chlorides,if Z=Cl, derived from isonipecotic acid or nipecotic acid in thepresence of an aprotic solvent, but not limited to, such asdichloromethane and an organic base, such as diisopropylethylamine ortriethylamine.

The acylation can also be performed starting from an ester derived fromisonipecotic or nipecotic acid (Z=OR), when R is a good leaving group,such as p-nitrophenyl or ethyltrifluoroacetate using catalytic basicconditions

Before the reduction of the amido group, the deprotection of the aminogroup can be achieved by hydrolysis of the carbamate or by hydrogenationof the benzyl group, using conventional methods. The reduction of theamido group can be performed in the presence of a hydride, such asLiAlH₄ or a borane in a dry polar aprotic solvent, such astetrahydrofuran, as shown in Scheme 3.

Where convenient, compounds of Formula (II) from compounds of Formula(VI) can be obtained by a reduction of the amido group before thedeprotection of the amino group.

Compounds of Formula (II) can also be obtained by reductive amination ofcompounds of Formula (IV) with amino protected piperidinecarboaldehydes(VIIIa) or (VIIIb) in the presence of a hydride, such as NaBH(OAc)₃(Scheme 4). The commercially available aldehydes (VIIIa) and (VIIIb)with the amino group protected are those with a carbamate, such as BOCor CBZ or with a benzyl group. The deprotection of the amino group byconventional methods can lead to desired compounds of Formula (II).

Compounds of Formula (II) can also be prepared by the alkylation ofcompounds of Formula (IV) with hydroxymethyl piperidines with the aminogroup protected (IXa) or (IXb), after a derivatization of the hydroxygroup into a good leaving group Y (Xa) or (Xb).

For example, the transformation of the hydroxy group into an alkyl oraryl sulfonate can be performed in the presence of a sulfonic anhydride,such as methanesulfonic anhydride in an organic aprotic solvent, such asdichloromethane or toluene and an organic base, such as triethylamine ordiisopropylamine. The transformation can also be carried out with asulfonic acid chloride in the presence of an aprotic solvent, such asdichloromethane in the presence of an organic base, such asdiisopropylethylamine or triethylamine. Other transformations into abromine, iodine or chlorine can be achieved by other conventionalmethods.

The alkylation of compounds of Formula (IV) with compounds of Formula(X) (Scheme 5) can be performed in the presence of an appropriate baseand solvent. Useful bases include, but are not limited to, metalcarbonates such as K₂CO₃ or Cs₂CO₃, metal hydroxides, hindered alkoxidesor tertiary organic amines. Typical solvents include polar aproticliquids such as DMF or THF, or protic liquids such as alcohols. Thedeprotection of the amino group can be achieved by conventional methods.

Some compounds of Formula (I) can also be prepared by the coupling ofcompounds of Formula (XIa) or (XIb) or their acid derivatives or by thecoupling of compounds of Formula (XIc) or (XId):

in which W is as defined in Formula (I), Z can be as it was describedfor compounds (Va) or (Vb) and Y can be as it was described forcompounds (Xa) or (Xb), with a compound of a Formula (IV):

in which R¹-R⁷ are as defined in Formula (I).

The coupling can be performed using the same methods and conditionsdescribed for the coupling of compounds of Formula (IV) with compoundsof Formula (Va) or (Vb) and for the coupling of compounds of Formula(IV) with compounds of Formula (Xa) or (Xb).

Compound (IV) is prepared as it was described above. Compounds ofFormula (XIa) and (XIb) can be synthesized by the coupling ofisonipecotic and nipecotic acid with compounds of Formula (III) in anaprotic solvent, such as dichloromethane or toluene in the presence ofan organic base, such as diisopropylethylamine or triethylamine.Compounds of Formula (XIc) and (XId) can be obtained from deprotectedpiperidines (Xa) and (Xb) by coupling with compounds of Formula (III)using similar conditions described above.

The obtained reaction products may, if desired, be purified byconventional methods, such as crystallisation, chromatography andtrituration. Where the above described processes for the preparation ofcompounds of the invention give rise to mixtures of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. If there are chiral centers the compounds may beprepared in racemic form, or individual enantiomers may be preparedeither by enantiospecific synthesis or by resolution.

One preferred pharmaceutically acceptable form is the crystalline form,including such form in pharmaceutical composition. In the case of saltsand solvates the additional ionic and solvent moieties must also benon-toxic. The compounds of the invention may present differentpolymorphic forms, it is intended that the invention encompasses allsuch forms.

Another aspect of this invention relates to a method of treating orpreventing an 5-HT₇ mediated disease which method comprisesadministering to a patient in need of such a treatment a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticalcomposition thereof. Among the 5-HT₇ mediated diseases that can betreated are diseases caused by failures in central and peripheralserotonin-controlling functions, such as pain, sleep disorder, shiftworker syndrome, jet lag, depression, seasonal affective disorder,migraine, anxiety, psychosis, schizophrenia, cognition and memorydisorders, neuronal degeneration resulting from ischemic events,cardiovascular diseases such as hypertension, irritable bowel syndrome,inflammatory bowel disease, spastic colon or urinary incontinence.

The present invention further provides pharmaceutical compositionscomprising a compound of this invention, or a pharmaceuticallyacceptable salt, derivative, prodrug or stereoisomers thereof togetherwith a pharmaceutically acceptable carrier, adjuvant, or vehicle, foradministration to a patient.

Examples of pharmaceutical compositions include any solid (tablets,pills, capsules, granules etc.) or liquid (solutions, suspensions oremulsions) composition for oral, topical or parenteral administration.

In a preferred embodiment the pharmaceutical compositions are in oralform, either solid or liquid. Suitable dose forms for oraladministration may be tablets, capsules, syrups or solutions and maycontain conventional excipients known in the alt such as binding agents,for example syrup, acacia, gelatin, sorbitol, tragacanth, orpolyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch,calcium phosphate, sorbitol or glycine; tabletting lubricants, forexample magnesium stearate; disintegrants, for example starch,polyvinylpyrrolidone, sodium starch glycollate or microcrystallinecellulose; or pharmaceutically acceptable wetting agents such as sodiumlauryl sulfate.

The solid oral compositions may be prepared by conventional methods ofblending, filling or tabletting. Repeated blending operations may beused to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are conventionalin the art. The tablets may for example be prepared by wet or drygranulation and optionally coated according to methods well known innormal pharmaceutical practice, in particular with an enteric coating.

The pharmaceutical compositions may also be adapted for parenteraladministration, such as sterile solutions, suspensions or lyophilizedproducts in the appropriate unit dosage form. Adequate excipients can beused, such as bulking agents, buffering agents or surfactants.

The mentioned formulations will be prepared using standard methods suchas those described or referred to in the Spanish and US Pharmacopoeiasand similar reference texts.

Administration of the compounds or compositions of the present inventionmay be by any suitable method, such as intravenous infusion, oralpreparations, and intraperitoneal and intravenous administration. Oraladministration is preferred because of the convenience for the patientand the chronic character of the diseases to be treated.

Generally an effective administered amount of a compound of theinvention will depend on the relative efficacy of the compound chosen,the severity of the disorder being treated and the weight of thesufferer. However, active compounds will typically be administered onceor more times a day for example 1, 2, 3 or 4 times daily, with typicaltotal daily doses in the range of from 0.1 to 1000 mg/kg/day.

The compounds and compositions of this invention may be used with otherdrugs to provide a combination therapy. The other drugs may form part ofthe same composition, or be provided as a separate composition foradministration at the same time or at different time.

The following descriptions and examples illustrate, but do not limited,the preparation of the compounds of the invention.

EXAMPLES

The starting materials of general formula (I) were prepared by means ofconventional organic chemistry methods known to those skilled in theart. The preparation of some of the intermediates of general formulas(II), (IV), (VI) and (VII) is shown below:

Example A

This example illustrate the preparation of a compounds of generalformula (IV).

6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride

This compound is well described in the literature (The Pictet-Spenglersynthesis of tetrahydroisoquinolines and related compounds. Wilson M.Whaley and Tuticorin R. Govindachari. Organic Reactions, vol 6, chapter3. John Wiley & Sons, Inc) and is prepared by a Pictet-Spenglerreaction.

A solution of 35% formaldehyde (2.49 g, 0.034 mol) was added dropwise to2-(3-methoxyphenyl)ethanamine (5 g, 0.033 mol). The warm solution soondeposited an oil and the reaction was completed by heating the mixturefor one hour at 100° C. The oil was extracted with toluene (25 ml) andwashed with water (3×18 ml). The extract was dried over Na₂SO₄ and thesolvent was concentrated to yield a yellow oil. A solution of 20%hydrochloric acid (6 ml) was added to the crude and the mixture wasstirred at 100° C. for 1 hour. After the evaporation to dryness, theresidue was dissolved in a little water, made alkaline with concentratedpotassium hydroxide, extracted with dichloromethane (3×90 ml) and driedover Na₂SO₄. After the evaporation of the solvent, the oil was dissolvedin ethyl acetate and concentrated hydrochloric acid was added to formthe hydrochloride, which was filtered to yield a white solid identifiedas 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.1 g, 80%yield).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.96 (m, 2H) 3.31 (m, 2H) 3.72 (s, 3H)4.14 (m, 2H) 6.80 (m, 2H) 7.11 (d, J=8.35 Hz, 1H) 9.39 (br, 2H)

MS (APCI (M+H)⁺):163

Example B

This example illustrate the preparation of a compound of general formula(VIa).

4-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-piperidine-1-carboxylicacid tert-butyl ester

DCC (2.16 g, 0.011 mol), a catalytic amount of DMAP (0.098 g, 8 mmol)and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.04 g, 0.009mol) were added to a solution of6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline (1.31 g, 0.008 mol) indichloromethane (30 ml). The clear solution soon deposited a white solidcorresponding to the cyclohexyl urea formation. The crude was stirredfor 2 hours at room temperature. The solid was filtered and the crudewas washed with water and dried over Na₂SO₄. The solvent was vacuumconcentrated and the residue was purified by flash chromatography usinga gradient consisting of different mixtures of dichloromethane/methanolto give puretert-Butyl-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidine-1-carboxy-lateas yellow solid (3.8 g, 85% yield).

¹H NMR (300 MHz, DMSO-d₆) d ppm 1.38 (s, 9H) 1.41 (m, 2H) 1.58 (m, 2H)2.63 (m, 1H) 2.75 (m, 2H) 2.88 (m, 2H) 3.62 (m, 1H) 3.69 (s, 6H) 3.70(m, 1H) 3.92 (m, 2H) 4.48 (s, 1H) 4.62 (s, 1H) 6.74 (m, 2H)

MS (APCI (M+H)⁺):405

Example C

This example illustrate the preparation of a compound of general formula(VIIa).

(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-piperidin-4-yl-methanonehydro-chloride

A solution of 5 N hydrochloric acid in Et₂O (15 ml) was added to asolution of4-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinoline-2-carbonyl)-piperidine-1-carboxylicacid tert-butyl ester (3 g, 7.43 mmol) in ethyl acetate and the mixturewas stirred for 2 hours at room temperature. The precipitate formed wascollected by filtration and the white solid obtained was identified as(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(piperidin-4-yl)-methanonehydrochloride (2.1 g, 95% yield).

¹H NMR (400 MHz, DMSO-d₆) 8 ppm 1.76 (m, 4H) 2.64 (t, J=5.86 Hz, 1H)2.75 (t, J=5.47 Hz, 1H) 2.92 (m, 2H) 3.02 (m, 1H) 3.24 (m, 2H) 3.63 (m,1H) 3.69 (m, 7H) 4.49 (s, 1H) 4.62 (s, 1H) 6.74 (m, 2H) 8.76 (br, 1H)

MS (APCI (M+H)⁺): 305

Example D

This example illustrate the preparation of a compound of general formula(IIa).

6,7-dimethoxy-2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolinedihydrochloride

A 1 M solution of LiAlH₄ in dry tetrahydrofuran (38 ml) was addeddropwise to a solution of(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(piperidin-4-yl)methanone(3.1 g, 10.0 mmol) in dry tetrahydrofuran (77 ml) under argonatmosphere. The mixture was refluxed overnight. A solution of saturatedsodium tartrate (250 ml) was added to the crude and the mixture isstirred for 1 hour. Then, extracted with ethyl acetate (3×120 ml), driedover Na₂SO₄, filtered and evaporated to dryness to afford a white solid(2.75 g, 92% yield). The solid is dissolved in ethyl acetate and a 2.8 Msolution of hydrogen chloride in ethanol was then added. The precipitateformed was collected by filtration to giveEthyl-[3-(7,8-Dimethoxy-2,2a,4,5-tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propyl]-aminedihydro-chloride (2.69 g, 73% yield) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.44 (m, 2H) 2.00 (m, 2H) 2.20 (m, 1H)2.86 (m, 3H) 3.09 (m, 2H) 3.26 (m, 4H) 3.61 (m, 1H) 3.71 (s, 3H) 3.72(s, 3H) 4.13 (m, 1H) 4.44 (d, J=13.62 Hz, 1H) 6.74 (s, 1H) 6.80 (s, 1H)8.94 (m, 2H) 10.72 (br, 1H)

MS (APCI (M+H)⁺): 291

Example E

This example illustrate the preparation of a compound of general formula(Ia).

2-((1-(2,5-dichlorophenylsulfonyl)piperidin-4-yl)methyl)-1,2,3,4-tetrahydroisoquinolinehydrochloride (3)

2,5-dichlorobenzene-1-sulfonyl chloride (108.1 mg, 0.44 mmol) was addedto a solution of 2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolinedihydrochloride (92.1 mg, 0.40 mmol) and N,N-diisopropylethylamine(206.9.2 mg, 1.60 mmol) in CH₂Cl₂ (10 mL) and the mixture was stirredovernight at room temperature. The resulting solution was washed withwater (3×10 mL), dried over Na₂SO₄, and evaporated to dryness. The freebase was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogenchloride in ethanol (0.10 mL) was then added. The product wascrystallized and collected by filtration, and vacuum dried to give awhite solid (138 mg, 78%).

¹N NMR (300 MHz, DMSO-d6) d ppm: ¹H NMR (300 MHz, DMSO-d6) δ ppm 1.21(m, 2H) 1.90 (m, 2H) 2.08 (m, 1H) 2.76 (m, 2H) 3.01 (m, 1H) 3.10 (m, 2H)3.24 (m, 2H) 3.65 (m, 1H) 3.75 (d, J=12.45 Hz, 2H) 4.23 (dd, J=15.30,7.83 Hz, 1H) 4.53 (d, J=14.94 Hz, 1H) 7.15 (m, 1H) 7.24 (m, 3H) 7.77 (m,2H) 7.94 (m, 1H) 10.22 (br, 1H)

MS (APCI (M+H)⁺): 439

Example F

This example illustrate the preparation of a compound of general formula(Ia).

2-((1-(2,5-dichlorophenylsulfonyl)piperidin-4-yl)methyl)-6,7-dimethoxy-1,2,3,4-tetra-hydroisoquinolinehydrochloride (77)

2-Chlorobenzene-1-sulfonyl chloride (301.9 mg, 1.43 mmol) was added to asolution of2-(piperidin-4-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinedihydrochloride (472 mg, 1.3 mmol) and N,N-diisopropylethylamine (1.3ml, 7.5 mmol) in CH₂Cl₂ (25 mL) and the mixture was stirred overnight atroom temperature. The resulting solution was washed with water (3×30mL), dried over Na₂SO₄, and evaporated to dryness. The free base wasdissolved in ethyl acetate (2 ml). A 2.8 M solution of hydrogen chloridein ethanol (0.6 mL) was then added. The product was crystallized andcollected by filtration, and vacuum dried to give a white solid (406 mg,63%).

¹H NMR (300 MHz, DMSO-d6) d ppm: 1H NMR (300 MHz, DMSO-d₆) 8 ppm 1.25(m, 2H) 1.89 (m, 2H) 2.06 (m, 1H) 2.71 (t, J=11.21 Hz, 2H) 2.88 (m, 1H)3.13 (m, 4H) 3.60 (dd, J=11.43, 4.83 Hz, 1H) 3.70 (s, 3H) 3.71 (s, 3H)3.74 (m, 2H) 4.11 (dd, J=15.45, 7.84 Hz, 1H) 4.41 (d, J=14.65 Hz, 1H)6.72 (s, 1H) 6.79 (s, 1H) 7.57 (m, 1H) 7.70 (m, 2H) 7.97 (dd, J=7.76,1.17 Hz, 1H) 10.16 (br, 1H)

MS (APCI (M+H)⁺): 465

The spectroscopic data for the identification of some of the sulfonamidecompounds of the invention having general formula (I), preparedanalogously to the methods described in the above examples, are shown inthe following table 1:

MS (APCI (M + N^(o) STRUCTURE Autonom ¹H-NMR H)⁺) 1

2-[1-(5-Chloro-2,4-difluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride1H NMR (300 MHz,DMSO-D6) δ ppm 1.23(m, 2 H) 1.91 (m, 3 H)2.58 (t, J =11.57 Hz,2 H) 3.00 (m, 1 H) 3.09(m, 2 H) 3.24 (m, 2 H)3.68 (m, 3 H) 4.21(m,1 H) 4.51 (d, J =14.06 Hz, 1 H) 7.15 (m,1 H) 7.23 (m, 3 H) 7.96(m, 2H) 10.24 (br, 1 H) 441 2

2-[1-(2-Chloro-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride1H NMR (300 MHz,DMSO-D6) δ ppm 1.23(m, 2 H) 1.90 (m, 2 H)2.06 (m, 1 H)2.71 (m,2 H) 3.01 (m, 1 H) 3.09(m, 2 H) 3.19 (m, 2 H)3.69 (m, 3 H) 4.23(m,1 H) 4.52 (d, J =16.11 Hz, 1 H) 7.15(m, 1 H) 7.24 (m, 3 H)7.56 (m, 1H)7.70 (m, 2 H) 7.97 (d,J = 7.91 Hz, 1 H) 10.19(br, 1 H) 405 3

2-[1-(2,5-Dichloro-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 1H NMR (300 MHz,DMSO-D6) δ ppm 1.21(m, 2 H) 1.90 (m, 2H)2.08 (m, 1 H) 2.76 (m,2 H) 3.01 (m, 1 H) 3.10(m, 2 H) 3.24 (m, 2H)3.65 (m, 1 H) 3.75 (d,J = 12.45 Hz, 2 H) 4.23(dd, J = 15.30,7.83 Hz, 1H) 4.53 (d,J = 14.94 Hz,1 H) 7.15 (m, 1 H) 7.24(m, 3 H) 7.77 (m, 2H)7.94 (m, 1 H) 10,22(br, 1 H) 439 4

2-(1-Benzenesulfonyl-piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolinehydrochloride371 5

2-[1-(Toluene-3-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride1H NMR (300 MHz,DMSO-D6) δ ppm 1.24(m, 2 H) 1.89 (m, 3 H)2.18 (t, J =11.27 Hz,2 H) 2.40 (s, 3 H) 2.97(m, 1 H) 3.04 (m, 2 H)3.22 (m, 2 H) 3.61(m,3 H) 4.19 (m, 1 H) 4.49(d, J = 12.01 Hz,1 H) 7.11 (m, 1 H) 7.21(m, 3H) 7.52 (m, 4 H)10.18 (br, 1 H) 385 6

2-[1-(2-Chloro-4,5-difluoro-benzene-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride1H NMR (300 MHz,DMSO-D6) δ ppm 1.21(m, 2 H) 1.88 (m, 2 H)2.05 (m, 1 H)2.77 (m,2 H) 3.01 (m, 1 H) 3.09(m, 2 H) 3.25 (m, 2 H)3.63 (m, 1 H) 3.73(d,J = 12.30 Hz, 2 H)4.22 (dd, J = 16.03,7.10 Hz, 1 H) 4.52 (d,J = 13.62Hz,1 H) 7.15 (m, 1 H) 7.23(m, 3 H) 8.05 (m, 2 H)10.26 (br, 1 H) 441 7

2-[1-(5-Chloro-2,4-difluoro-benzene-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride441 8

2-[1-(2-Chloro-benzenesulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 405 9

2-[1-(2,5-Dichloro-benzenesulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride439 10

2-(1-Benzenesulfonyl-piperidin-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolinehydrochloride 371 11

2-[1-(Toluene-3-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydroiso-quinolinehydrochloride 1H NMR (300 MHz,DMSO-D6) δ ppm 1.23(m, 2 H)1.72 (m, 1 H)2.18 (m, 1 H)2.27 (m, 2 H) 2.40 (s, 3 H)3.04 (m, 3 H) 3.21 (m,2 H) 3.69(m, 3 H) 4.21(m, 1 H) 4.55 (m, 1 H)7.25 (m, 4 H) 7,52 (m,3 H) 7.55 (m, 1H) 10.22(br, 1 H) 385 12

2-[1-(2-Chloro-4,5-difluoro-benzenesulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride441 13

2-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride433 14

2-[1-(3-Chloro-4-fluorobenzene-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride1H NMR (300 MHz,DMSO-D6) δ ppm1.09 (m, 1 H) 1.55 (m,1 H) 1.72 (m, 2 H)2.23(d, J = 8.64 Hz,2 H) 2.42 (m, 1 H) 3.08(m, 3 H) 3.23 (m, 2 H)3.44(m, 1 H) 3.68 (m,2 H) 4.27 (dd, J =16.03, 7.39 Hz, 1 H)4.55 (m, 1 H)7.26(m, 4 H) 7.75 (m, 2 H)7.95 (m, 1 H) 10.32 (br,1 H) 423 15

2-[1-(5-Fluoro-2-methyl-benzene-sulfonyl)-piperidin-3-tetrahydroisoquinolinehydrochloride403 16

2-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride1H NMR (300 MHz,DMSO-D6) δ ppm 1.22(m, 2 H) 1.90 (m, 2 H)2.04 (m, 1 H)2.36 (s,3 H) 2.50 (s, 3 H) 2.55(m, 2 H) 3.01 (m, 1 H)3.09 (m, 2 H) 3.25(m,2 H) 3.63 (m, 3 H) 4.22(dd, J = 15.45,7.83 Hz, 1 H) 4.52 (d,J = 15.67Hz,1 H) 7.15 (m, 1 H) 7.24(m, 3 H) 7.57 (s, 1 H)7.75 (s, 1 H) 10.28(br,1 H) 433 17

2-[1-(3-Chloro-4-fluoro-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride423 18

2-[1-(5-Fluoro-2-methyl-benzene-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride403 19

2-[1-(2-Brorno-benzenesulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 449 20

2-[1-(Naphthalene-1-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride421 21

2-[1-(Thiophene-2-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride377 22

2-[1-(2-Bromo-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride1H NMR (300 MHz,DMSO-D6) δ ppm 1.23(m, 2 H) 1.89 (m, 2 H)2.06 (m, 1 H)2.74 (m,2 H) 3.02 (m, 1 H) 3.10(m, 2 H) 3.26 (m, 2 H)3.69 (m, 3 H) 4.24(m,1 H) 4.53 (d, J =16.72 Hz, 1 H) 7.16(m, 1 H) 7.23 (m, 3 H)7.58 (qd, J= 7.10,1.68 Hz, 2 H) 7.88 (dd,J = 7.82, 1.76 Hz,1 H) 7.99 (dd, J =7.47.2.05 Hz, 1 H)10.13 449 23

2-[1-(Naphtalene-1-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride1H NMR (300 MHz,DMSO-D6) δ ppm 1.22(m, 2 H) 1.92 (m, 3 H)2.44 (m, 2 H)2.97 (m,1 H) 3.03 (m, 2 H) 3.19(m, 2 H) 3.59 (m, 1 H)3.75 (m, 2 H) 4.17(dd,J = 15.23, 5.86 Hz,1 H) 4.47 (d, J =17.28 Hz, 1 H) 7.10 (m,1 H) 7.20(m, 3 H) 7.70(m, 3 H) 8.12 (t, J =7.83 Hz, 2 H) 8.29 (d,J = 8.05 Hz,1H)8.68 (d, J = 8.49 Hz, 1 421 24

2-[1-(Thiophene-2-sulfonyl)piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride377 25

2-[1-(2,4,5-Trichloro-benzenesulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride473 26

2-[1-(2,4,5-Trichloro-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride1H NMR (300 MHz,DMSO-D6) δ ppm 1.21(m, 2 H) 1.89 (m, 2 H)2.06 (m, 1 H)2.78 (m,2 H) 3.02 (m, 1 H) 3.10(m, 2 H) 3.26 (m, 2 H)3.63 (m, 1 H) 3.75(d,J = 12.45 Hz, 2 H) 4.23(dd, J = 15.37,6.74 Hz, 1 H) 4.52 (m,1 H) 7.16(m, 1 H) 7.24(m, 3 H) 8.10 (s, 1 H)8.18 (s, 1 H)10.13 (br 1 H) 473 27

2-[1-(4-Fluoro-naphtalene-1-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride439 28

2-[1-(Biphenyl-2-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride447 29

2-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 413 30

2-[1-(Dibenzofuran-2-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride461 31

2-[1-(2-Methoxy-4-methyl-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride415 32

2-[1-(5-Isoxazol-5-yl-thiophene-2-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride 444 33

2-[1-(4-Fluoro-naphthalene-1-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride439 34

2-[1-(Biphenyl-2-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride447 35

2-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 413 36

2-[1-(Dibenzofuran-2-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinoline461 37

2-[1-(2-Methoxy-4-methyl-benzenesulfonyl)-piperidin-3-ylmethyl]-l,2,3,4-tetrahydro-isoquinolinehydrochloride415 38

2-[1-(5-Isoxazol-5-yl-thiophene-2-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride 444 39

6-[4-(3,4-Dihydro-1H-isoquinolin-2-yl-methyl)-piperidine-1-sulfonyl]-3H-benzooxazol-2-one442 40

2-[1-(7-Methyl-benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride443 41

5-[4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-2-fluoro-benzoicacidhydrochloride 433 42

2-[1-(3Chloro-4-methoxy-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride435 43

6-[4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-3,4-dihydro-1H-quinolin-2-one440 44

6-[4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-3H-benzothiazol-2-one444 45

1{4-[4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-phenyl}-ethanonehydrochloride413 46

5-[4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-6-methyl-1H-pyrimidine-2,4-dione419 47

7-[4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-1,5-dihydrobenzo[b][1,4]-diazepine-2-dionehydrochloride469 48

6-[4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-1,4-dimethyl-1,4-dihydroquinoxaline-2,3-dione483 49

2-[1-(1H-Imidazole-4-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinoline361 50

2-[1-(4-Fluoro-3-methyl-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride399 51

6-[4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-3H-benzooxazol-2-onehydrochloride428 52

2-[1-(4-Cyclohexyl-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochlo-ride453 53

8-[4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-quinolinehydrochloride 422 54

2-[1-(4-Chloro-naphtalene-1-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride455 55

8-[4-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-quinolinehydrochloride 422 56

2-[1-(4-Chloro-naphtalene-1-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride455 57

6-[3-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-3-methyl-3H-benzooxazol-2-onehydrochlo-ride 442 58

2-[1-(7-Methyl-benzo[1,2,5]thiadiazole-4-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride443 59

5-[3-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-2-fluoro-benzoicacidhydrochloride 433 60

2-[1-(3Chloro-4-methoxy-benzenesulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochlo-ride435 61

6-[3-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyll-3,4-dihydro-1H-quinolin-2-one440 62

6-[3-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-3H-benzothiazol-2-onehydrochloride444 63

1{4-[3-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-phenyl}-ethanonehydrochloride413 64

5-[3-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-6-methyl-1H-pyrimidine-2,4-dione419 65

7-[3-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-1,5-dihydrobenzo[b][1,4]diazepine-2-dione469 66

6-[3-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-1,4-dimethyl-1,4-dihydroquinoxaline-2,3-diane483 67

2-[1-(1H-Imidazole-4-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinoline361 68

2-[1-(4-F1uoro-3-methyl-benzenesulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinoline403 69

6-[3-(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-3H-benzooxazol-2-onehydrochloride428 70

2-[1-(4-Cyclohexyl-benzenesulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochlo-ride453 71

6,7-Dimethoxy-2-[1-(toluene-3-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 481 72

6-Methoxy-2-[1(toluene-3-sulfonyl)piperidin-4-ylmethyl]-1,2,3,4-tetra-hydroisoquinolinehydrochloride415 73

2-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-piperidin-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride473 74

2-[1-(2,3-Dihydro-benzofuran-5-sulfonyl)-piperidin-4-ylmethyl]-6-methoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride443 75

2-[1-(4-Chloro-2,5-dimethylbenzene-sulfonyl)-piperidin-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride493 76

2-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-4-ylmethyl]-6-methoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride 463 77

2-[1-(2-Chlorobenzene-sulfonyl)-piperidin-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride1H NMR (300 MHz,DMSO-d₆) δ ppm 1.25(m, 2 H) 1.89 (m, 2 H)2.06 (m, 1 H)2.71 (t,J = 11.21 Hz, 2 H)2.88 (m, 1 H) 3.13 (m,4 H) 3.60 (dd, J =11.43,4.83 Hz, 1 H), 3.70 (s, 3 H)3.71 (s, 3 H)3.74 (m, 2 H) 4.11 (dd,J= 15.45,7.84 Hz, 1 H) 4.41 (d,J = 14.65 Hz, 1 H)6.72 (s, 1 H) 6.79 (s,1H) 7.57 (m, 1 H) 7.70(m, 2 H) 7.97 (dd, J =7.76, 1.17 Hz, 1 H)10.16 (br,1 H) 465 78

2-[1-(2-Chlorobenzene-sulfonyl)-piperidin-4-ylmethyl]-6-methoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride 435 79

6-Methoxy-2-[1-(naphthalene-1-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 451 80

6-Methoxy-2-[1-(toluene-4-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride415 81

2-[1-(2,5-Dichloro-benzenesulfonyl)-piperidin-4-ylmethyl]-6-methoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride 469 82

8-[4-(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-quinolinehydrochloride452 83

6,7-Dimethoxy-2-[1-(toluene-4-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 445 84

6,7-Dimethoxy-2-[1-(naphthalene-1-sulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydroisoquinolinehydrochloride481 85

2-[1-(2,5-Dichloro-benzenesulfonyl)-piperidin-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride 1H NMR (300 MHz,DMSO-d₆) δ ppm1.22 (m,2 H) 1.89 (m, 2 H)2.05(m, 1 H) 2.76 (m, 2 H)2.91 (m, 1 H), 3.07 (m,2 H) 3.15 (m, 1 H)3.60(m, 2 H) 3.70 (s, 3 H)3.72 (s, 3 H) 3.77 (m,2 H) 4.11 (dd, J =15.23,7.18 Hz, 1 H) 4.41 (d,J = 13.62 Hz, 1 H)6.73 (s, 1 H) 6.79 (s,1 H) 7.77(td, J =7.80, 5.35 Hz,2 H) 7.93(m, 1 H) 10.21(br, 1 H) 499 86

2-[1-(3-Chloro-4-methoxy-benzenesulfonyl)-piperidin-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride495 87

6-Methoxy-2-[1-(4-methoxy-benzenesulfonyl)piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 431 88

6-Methoxy-2-[1-(2-methoxy-4-methyl-benzenesulfonyl)-piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride445 89

2-(1-Benzenesulfonyl-piperidin-4-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline431 90

8-[4-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-quinolinehydrochloride482 91

2-[1-(2,5-Dimethoxy-benzenesulfonyl)-piperidin-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride 491 92

6,7-Dimethoxy-2-[1-(4-methoxy-benzenesulfonyl)piperidin-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 461 93

2-[1-(2,5-Dichloro-benzenesulfonyl)-piperidin-3-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride499 94

2-[1-(2-Chloro-benzenesulfonyl)-piperidin-3-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride465 95

2-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)piperidin-3-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride493 96

6,7-Dimethoxy-2-[1-(naphthalene-1-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 481 97

8-[3-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-quinolinehydrochloride482 98

6,7-Dimethoxy-2-[1-(toluene-4-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride 445 99

2-(1-Benzenesulfonyl-piperidin-3-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinehydrochloride431 100

6,7-Dimethoxy-2-[1-(toluene-3-sulfonyl)1,2,3,4-tetrahydro-isoquinolinehydrochloride 445 101

2-[1-(2,5-Dichloro-henzenesulfonyl)-piperidin-3-ylmethyl]-6-methoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride 469 102

2-[1-(2-Chloro-benzenesuffonyl)-piperidin-3-ylmethyl]-6-methoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride 435 103

2-[1-(4-Chloro-2,5-dimethyl-benzenesulfonyl)-piperidin-3-ylmethyl]-6-methoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride 463 104

6-Methoxy-2-[1-(naphthalene-1-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinoline hydrochloride 451 105

8-[3-(6-Methoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-piperidine-1-sulfonyl]-quinolinehydrochloride452 106

6-Methoxy-2-[1-(toluene-4-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride415 107

2-(1-Benzenesulfonyl-piperidin-3-ylmethyl-6-methoxy-1,2,3,4-tetrahydro-isoquinolinehydrochloride 401 108

6-Methoxy-2-[1-(toluene-3-sulfonyl)-piperidin-3-ylmethyl]-1,2,3,4-tetrahydro-isoquinolinehydrochloride415

Biological Assays Radioligand Binding

Radioligand binding assays were performed using the Cloned HumanSerotonin Receptor, Subtype 7 (h5HT₇), expressed in CHO cells, coated onFlashplate (Basic FlashPlate Cat.: SMP200) from PerkinElmer (Cat.:6120512). The protocol assay was essentially the recommended protocol inthe Technical Data Sheet by PerkinEmer Life and Analytical Sciences. TheMass membrane protein/well was typically 12 μg and the Receptor/well wasabout 9-10 fmoles. The Flashplate were let equilibrate at roomtemperature for one hour before the addition of the components of theassay mixture. The binding buffer was: 50 mM Tris-HCl, pH 7.4,containing 10 mM MgCl₂, 0.5 mM EDTA and 0.5% BSA. The radioligand was[¹²⁵I]LSD at a final concentration of 0.82 nM. Nonspecific binding wasdetermined with 50 μM of Clozapine. The assay volume was 25 μl.TopSeal-A were applied onto Flashplate microplates and they wereincubated at room temperature for 240 minutes in darkness. Theradioactivity were quantified by liquid scintillation spectrophotometry(Wallac 1450 Microbeta Trilux) with a count delay of 4 minutes prior tocounting and a counting time of 30 seconds per well. Competition bindingdata were analyzed by using the LIGAND program (Munson and Rodbard,LIGAND: A versatile, computerized approach for characterization ofligand-binding systems. Anal. Biochem. 107: 220-239, 1980) and assayswere performed in triplicate determinations for each point. Results forrepresentative compounds are given in the table 2 below:

TABLE 2 COMPOUND 5-HT7 IC-50 (nM) 1 70.2 2 28.4 ± 18.2 3 76.4 5 63   618.2 ± 3.7  16 36.1 ± 16.0 22 16.8 ± 8.0  23 83.4 77 41.8 85 60.7

1. A compound of the formula I:

wherein W is a substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocyclyl; R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are each independentlyselected from the group formed by hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted aryl, substituted orunsubstituted heterocyclyl, —COR⁸, —C(O)OR⁸, —C(O)NR⁸R⁹, —HC═NR⁸, —CN,—OR⁸, —OC(O)R⁸, —S(O)_(t)—R⁸, —NR⁸R⁹, —NR⁸C(O)R⁹, —NO₂, —N═CR⁸R⁹ orhalogen; wherein t is 1, 2 or 3; R⁸ and R⁹ are each independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted aryl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted alkoxy, substituted orunsubstituted aryloxy, halogen; and the 1,2,3,4-tetrahydroisoquinolinegroup is linked through the methylene group to positions 3 or 4 of thepiperidine ring; or a pharmaceutically acceptable salt, isomer, prodrugor solvate thereof.
 2. A compound according to claim 1 characterized inthat 1,2,3,4-tetrahydroisoquinoline group is linked through metilene toposition 4 of the piperidine ring.
 3. A compound according to claim 1characterized in that W is an aromatic group selected from substitutedor unsubstituted aryl, substituted or unsubstituted heterocyclyl, orsubstituted or unsubstituted phenyl.
 4. A compound according to claim 3characterized in that W is selected from alkyl, alkoxy and/or halosubstituted phenyl.
 5. A compound according to claim 1 characterized inthat R⁵, R⁶ and R⁷ are H.
 6. A compound according to claim 1characterized in that R¹ and R⁴ are H.
 7. A compound according to claims5 or 6 wherein R² is alkoxy, and R³ is H or alkoxy.
 8. A process for thepreparation of a compound of formula (I) or a salt, isomer or solvatethereof as claimed in any of claims 1-7, which comprises coupling ofcompounds of Formula (IIa) or (IIb):

in which R¹-R⁷ are as defined in Formula (I), with a compound of Formula(III):

in which W is as defined in Formula (I) and X is an halogen, preferablyCl.
 9. A pharmaceutical composition which comprises a compound asdefined in any of claims 1-7 or a pharmaceutically acceptable salt,prodrug, isomer or solvate thereof, and a pharmaceutically acceptablecarrier, adjuvant or vehicle.
 10. A pharmaceutical composition accordingto claim 9 for oral administration.
 11. A method of manufacturing amedicament comprising combining a compound as defined in any of claims1-7 with a pharmaceutically acceptable carrier.
 12. A method of treatinga 5-HT₇ mediated disease or condition comprising administering acomposition according to claim
 11. 13. A method according to claim 12wherein the disease is sleep disorder, shift worker syndrome, jet lag,depression, seasonal affective disorder, migraine, anxiety, psychosis,schizophrenia, pain, cognition and memory disorders, neuronaldegeneration resulting from ischemic events, cardiovascular diseases,hypertension, irritable bowel syndrome, inflammatory bowel disease,spastic colon or urinary incontinence.
 14. A method for treating orpreventing a central nervous disorder comprising administering to apatient in need thereof a therapeutically effective amount of a compoundas defined in any of claims 1-7, or a pharmaceutically acceptable salt,isomer, prodrug or solvate thereof.
 15. A compound according to claim 2characterized in that W is an aromatic group selected from substitutedor unsubstituted aryl, substituted or unsubstituted heterocyclyl, orsubstituted or unsubstituted phenyl.
 16. A compound according to claim15 characterized in that W is selected from alkyl, alkoxy and/or halosubstituted phenyl.
 17. A compound according to claim 2 characterized inthat R⁵, R⁶ and R⁷ are H.
 18. A compound according to claim 3characterized in that R⁵, R⁶ and R⁷ are H.
 19. A compound according toclaim 4 characterized in that R⁵, R⁶ and R⁷ are H.
 20. A compoundaccording to claim 15 characterized in that R⁵, R⁶ and R⁷ are H.
 21. Acompound according to claim 16 characterized in that R⁵, R⁶ and R⁷ areH.
 22. A compound according to claim 2 characterized in that R¹ and R⁴are H.
 23. A compound according to claim 3 characterized in that R¹ andR⁴ are H.
 24. A compound according to claim 4 characterized in that R¹and R⁴ are H.
 25. A compound according to claim 5 characterized in thatR¹ and R⁴ are H.
 26. A compound according to claim 15 characterized inthat R¹ and R⁴ are H.
 27. A compound according to claim 16 characterizedin that R¹ and R⁴ are H.
 28. A compound according to claim 17characterized in that R¹ and R⁴ are H.
 29. A compound according to claim18 characterized in that R¹ and R⁴ are H.
 30. A compound according toclaim 19 characterized in that R¹ and R⁴ are H.
 31. A compound accordingto claim 20 characterized in that R¹ and R⁴ are H.
 32. A compoundaccording to claim 21 characterized in that R¹ and R⁴ are H.
 33. Acompound according to claim 5 wherein R² is methoxy, and R³ is H ormethoxy.
 34. A compound according to claim 6 wherein R² is methoxy, andR³ is H or methoxy.